Assessment of BMI in lymphoma plays an important role in staging as its presence upstage the disease to stage IV.
This study compares 18F-FDG PET/CT and BMB in evaluating bone marrow in 145 lymphoma patients, 88 cases were HL, and 57 cases were NHL.
BMB is an invasive technique that allows histologic examination for only a small bone marrow sample from the posterior iliac crest. This is in contrast to 18F-FDG PET/CT, which is a noninvasive technique that allows visualization of the entire bone marrow.
The blind BMB does not exclude BMI when infiltration is present in sites other than the posterior iliac crest [16].
When BMB is only used as the reference standard, the sensitivity of PET/CT declines [5]. This is why we used follow-up findings, CT changes, and local biopsy and or MRI findings in patients with negative BMB results as an additional standard for these patients.
Diffuse uptake is considered a controversial area in most of the studies. Most studies found that diffuse uptake in bone marrow in HL cases is associated with a negative BMB, while in most DLCL cases with diffuse bone marrow uptake, positive BMB were found [11, 17]. Others found a diffuse pattern in HL with BMI in a small percentage of cases [18, 19]. In our study, we found 2 cases with HL having diffuse bone marrow uptake and positive BMB results (Fig. 6). This is consistent with the study done by Chen-Liang et al. [20], who also detected 2 cases of HL having diffuse uptake and positive BMB findings. In our study, all the six cases of NHL with diffuse uptake had positive BMB results (Fig. 7). This is consistent with the study done by Khan et al. [12], who found five cases with diffuse uptake, all had positive BMB results. However, in the study done by Cortés-Romera et al. [16], four cases only out of nine cases with diffuse uptake pattern had positive BMB results. Also, in the study done by Cerci et al. [21], 4 cases only out of 18 cases with DLBCL had positive BMB results, so it was concluded that cases with diffuse FDG uptake should be biopsied to establish etiology.
PET/CT detected 24 (16.5%) cases with positive BMI that were missed by BMB. Local biopsy was done guided by PET/CT in seven cases (Fig. 8) and targeted MRI was done in five other patients, both confirmed bone marrow infiltration. Twenty cases had absent posterior iliac crest involvement in either side or four cases had unilateral posterior iliac crest involvement. It was interesting that we found the site of the biopsy taken was from the normal posterior iliac crest (Fig. 9).
PET/CT can detect infiltration in any region of the skeleton compared to the confined site of the posterior iliac crest by BMB. It can also guide the site of the biopsy in clinically warranted cases when management will differ.
The PET/CT showed a higher sensitivity of 95.6% (95% CI, 89.3-100%) than BMB 46.7% (95% CI, 31.5-61.8%) in detecting BMI and good specificity of 98% (95% CI, 95.2-100%) compared to that BMB 100%.The accuracy of PET/CT was 97.2% (95% CI, 94.5-99.9%) while that of BMB was 83.4% (95% CI, 77.3-89.6%).
This is consistent with the meta-analysis done by Wu et al. [22], who included 32 studies and found that PET/CT sensitivity and specificity were 91.6% (95% CI, 85.1, 95.9) and 90.3% (95% CI, 85.9, 93.7) respectively. PET/CT was found highly sensitive and specific modality in detecting bone marrow involvement in lymphoma.
This is against the meta-analysis study done by Pakos et al. [23], who included 587 patients, 18F-FDG PET/CT results did not show excellent concordance with that of BMB for detecting bone marrow infiltration. The sensitivity and specificity of PET/CT were found 51% (95% CI, 38–64%) and 91% (95% CI, 85–95%) respectively. BMB was only used as the gold standard in this meta-analysis, so18F-FDG PET/CT was not recommended for replacing the routine BMB in this meta-analysis.
In our study, we found moderate agreement between PET/CT and BMB results in assessment of bone marrow in the whole study using Cohen’s k computation. It was found 0.47 with p value less than 0.0001. As 117 (80.7%) patients showed concordant results between PET/CT and BMB and 28 (19.3%) showed discordant result. This is consistent with the previous studies in which the discordant rate was found ranged from 13.3 to 22.9% [1, 14, 16, 24,25,26,27].
In our study, there were 88 patients with Hodgkin lymphoma, 17 (19.3%) of them had BMI. BMB detected only 1 (1.1%) case that was not detected by PET/CT, but PET/CT detected 11 (12.5%) additional cases with bone marrow infiltration presented outside the site of the biopsy and therefore were missed by the BMB.
Our results showed a higher sensitivity of PET/CT 94.1% (95% CI, 81.6-100) in detection of BMI compared to BMB 35.3% (95% CI, 10-60.6). This is consistent with the study done by Cistaro et al. [28], the sensitivity of 18F-FDG PET/CT was found 96% (95% CI, 89-100%) while that of BMB was found 38% (95% CI, 20-57%). This is also consistent with the study done by Büyükşimşek et al. [29], who included 110 patients with HL and found PET/CT sensitivity was 91.3% (95% CI, 71.96-98.93) compared to that of BMB which was 56.52% (95% CI, 34.49-76.81).
In the study done by Agrawal et al. [30], who included 38 patients with HL, all were pediatrics, PET/CT detected BMI in 3 (8%) additional patients not detected by BMB. The calculated sensitivity, specificity, PPV, and NPV of FDG PET/CT for detection of BMI were 87.5%, 100%, 100%, and 96% respectively and the sensitivity, specificity, PPV, and NPV of BMB for BMI were 62.5%, 100%, 100%, and 88.4% respectively.
In the study done by Cheng et al. [1], who included 31 cases of pediatric HL. PET/CT detected BMI in 2 (6.5 %) additional patients not detected by BMB.
Purz et al. [31] compared the difference between BMB and F-18 FDG PET/CT in the detection of BMI in 175 HL pediatric patients all with stage more than IIA. They found that F-18 FDG PET/CT detected 22% of positive cases not detected by BMB and concluded that F-18 FDG PET may replace BMB in routine staging procedure.
This is also consistent with previous studies, which recommended preclusion of the routine use of BMB for staging in these patients [8, 17, 32, 33].
In our study, we found a fair agreement between PET/CT and BMB in HL cases by using Cohen’s k, it was found 0.350 with p value less than 0.0001. This is consistent with the study done by Cistaro et al. [28], who found also fair agreement between PET/CT and BMB findings as Cohen’s k was found 0.398 with p value less than 0.001.
In our study, there were 57 patients with non-Hodgkin lymphoma, 28 (49%) of them had BMI. Only one (1.8%) case was positive by BMB and was not detected by PET/CT but pathology of this patient was lymphoplasmacytic lymphoma, which is known to have limited and variable FDG avidity (Fig. 10). PET/CT detected 13 (22.8%) additional cases with positive BMI and negative BMB results. The sum of the concordant result of PET/CT and BMB was 43 (75.4%), and the discordant results were 14 (24.5%). This is consistent with the study done by Vishnu et al. [5], who included 99 cases of DLBCL, there were 38% of cases that had BMI. PET/CT was positive for BMI in 24 cases but BMB was positive in 14 cases. Two (2%) cases only were detected by BMB and were not detected by PET/CT while 12 (12%) patients were detected by PET/CT and were negative by BMB. The concordant results between PET/CT and BMB were 85 (86%). The discordant results between PET/CT and BMB were 14 (14%) patients.
Our results showed a higher sensitivity of PET/CT in NHL cases 96.4% (95% CI, 89.1-100) compared to BMB 53.6 (95% CI, 33.9-73.3) and perfect specificity 100% in both. The accuracy of PET/CT was 98.2% (95% CI, 94.7-100) while that of BMB was 77.2% (95% CI, 66-88.4).
This is consistent with the study made by Badr et al. [34], who included 27 patients with NHL and found the sensitivity of PET/CT was 100% while that of BMB was 42.9% and the specificity was 100% in both.
In the meta-analysis done by Adams et al. [11], who included seven studies assessing PET/CT for detection of BMI in DLBCL. They found that the PET/CT sensitivity was 78.4% (95% CI, 69.9-85.5%) and specificity was 99.7% (95% CI, 98.3-100%) when both focal and diffuse uptake were considered positive for bone marrow involvement as in our study.
This is against the study done by Adams and Kwee [35], who compared PET/CT and BMB of the posterior iliac crest and showed that PET/CT may be negative in the posterior iliac crest in up to 80% of cases with a positive BMB.
The role of both PET/CT and BMB in the assessment of BMI is complementary [25]. PET/CT can be used to guide the site of biopsy by the FDG uptake when lesions are present outside the routine iliac bone marrow sampling sites. Some studies suggest that routine BMB is still necessary in cases with a negative PET/CT scan result as PET/CT may miss early limited infiltration of the bone marrow, which can be detected by the BMB [16].
Limitations
The number of patients in our study was relatively small. We included a heterogeneous group of patients of HL and NHL. This has made our results for the separate calculation of the sensitivity, specificity, accuracy of PET/CT, and BMB in nodular sclerosis, mixed cellularity and DLBC types not accurate and should be evaluated with a larger sample size.
Most of the previous studies were done retrospectively, so local biopsy or targeted MRI were not done. From the strengths in our study is that it was done prospectively so guided local biopsy or targeted MR imaging were done in 12 (50%) patients with positive PET/CT and negative iliac crest BMB results. This helped to confirm the positive uptake detected by PET/CT. However, this was not done for all patients, as it was not possible to take another biopsy from another site in all patients, as it is an invasive technique accompanied by pain and anxiety. Also, not all cases could underwent further targeted MRI, as it should be recommended by the multidisciplinary team for special cases, who will really benefit from it and not to take the place of other patients with different diseases who are really in need for it.